viruses Review HIV Vaccine Development: 35 Years of Experimenting in the Funding of Biomedical Research Stuart Z. Shapiro Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, 5601 Fishers Lane, Rm 9C20B, Bethesda, MD 20892-9829, USA; [email protected]; Tel.: +1-240-292-6155; Fax: +1-240-627-3109 Academic Editor: Herve J. A. Fleury Received: 3 December 2020; Accepted: 17 December 2020; Published: 19 December 2020 Abstract: Funding vaccine development research is more complicated than simply putting out an announcement of funds available. The funders must decide whether product development can be accomplished by purely applied research, or whether more fundamental knowledge is needed before product development can be started. If additional basic knowledge is needed, identifying the specific area of the knowledge gap can be a challenge. Additionally, when there appears to be a clear path of applied research sometimes obstacles are encountered that require a return to more basic work. After deciding on the work to be done, funders must attract the scientists with the broad range of needed skills to cover all the stages of development. Collaborations must be promoted and alliances with other funders and industry must be developed. Funders use multiple tools and strategies to accomplish these tasks with varying success. Keywords: HIV-1; HIV vaccines; vaccinology; vaccine design; biomedical research funding 1. Introduction The rapidity with which vaccine developers have pivoted to working on COVID-19 vaccine development may have given many the impression that all that needs to be done to facilitate vaccine development for serious diseases is for funding agencies to announce the availability of funding. The several decades experience of funding HIV vaccine development demonstrates that it is not always that simple. Sometimes, the path to vaccine development appears to be clear. However, the market for some vaccines is so uncertain that the industry is not motivated to develop a vaccine, while academic scientists see an easy development path as too little a scientific challenge, or they do not even apply for funding because they fear the absence of a basic research challenge means grant applications will not be well received by peer reviewers. At the other extreme, the path to vaccine development is so unclear that the industry will not start the work until academic or government scientists have established the way. And often few academic researchers know where to start. In this situation, the challenge for the funders is to recruit the best scientists, with expertise in the newest technologies, to work in a field that may not promise quick results. In almost all cases, proper vaccine development, even when straightforward, is too large and complex a project to be easily divided into two-year to five-year grant programs, such as the standard grants available at the US National Institutes of Health (NIH). Furthermore, vaccine development is a complex process, which is beyond the capability of a single scientist. Before a vaccine candidate can be tested in people, it must be manufactured to current good manufacturing practice (cGMP) standards. Then, it must be tested in clinical trials for immunogenicity, safety and efficacy. Both activities involve different skill sets from those possessed by the vaccine product designers. Thus, building collaborations is extremely important. Funding agencies have developed many different tools to help vaccine developers get over these hurdles, and all of Viruses 2020, 12, 1469; doi:10.3390/v12121469 www.mdpi.com/journal/viruses Viruses 2020, 12, 1469 2 of 12 them have been used in the effort to develop an HIV vaccine over the past three decades. This article, written from the perspective of a Program Officer’s experiences in the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) at the US National Institutes of Health (NIH), will provide some detail about the tools NIAID employs, why and how they were applied in HIV vaccine development and to what extent they were useful. 2. HIV Vaccine Development Challenges Vaccine development for most infectious diseases is applied research (at the end of World War II, presidential science adviser, Vannevar Bush, laid out a conceptual framework for thinking about science and technology in which he drew a clear distinction between pure or basic research and applied research [1]). It starts with the observation of individuals who have been infected and subsequently recovered from disease by their own immune responses. If those curative responses could be induced by a vaccine before the individual is exposed to the pathogen the impact of the disease would be lessened or prevented completely. Thus, the analysis of immune responses of recovered individuals establishes the possibility of developing a vaccine guided by the quality, antigen or epitope specificity and quantity or titer of those responses. The vaccine developer then applies a small number of well-established, practical strategies (whole-killed, attenuated pathogen and surface protein or toxin subunit methodologies which have been refined and improved by decades of basic research [2] and, more recently, added to by the strategy of vector-based vaccines, thanks in no small part to HIV vaccine development funding [3]) to the task of developing a vaccine. Unfortunately for HIV vaccine development, no humans have cured themselves of HIV-1 infection. Additionally, HIV vaccine developers have long been hindered by the fact that HIV-1 does not replicate in any small animal model, and simian immunodeficiency virus (SIV) models do not allow direct testing of HIV vaccines. Despite these critical hurdles to standard vaccine development HIV vaccine developers started where most others start, with virus envelope protein vaccine candidates intended to induce neutralizing antibody responses to the only viral protein expressed on the virion surface. Quickly scientists came to understand that the extreme mutability of HIV-1 led to an enormous variety in virus envelopes to which the uninfected individual is exposed, likely precluding vaccine development based on a feasible number of envelope types. Thus, HIV vaccine development presents the challenge of inducing an unknown amount (or titer) of an unknown immune response to an unimaginable diversity of antigens without an animal model for preclinical testing. Clearly, the type of research required is beyond the usual “applied” research of vaccinology focused directly on vaccine product development. Neither is it the classical pure “basic” research that seeks to understand fundamental scientific problems without thought of immediate practical applications (the type of research performed with many unsolicited R01 NIH grant awards). What is required is a type of research that falls between basic and applied research, a research that looks to enhance basic knowledge to rapidly apply it to a practical problem. This is not a startlingly new concept at the NIH, as many biomedical scientists perform “basic” research essentially to apply their results to some specific disease. Such work has been called targeted basic research, purposive basic research, mission-oriented basic research, use-inspired basic research or, more recently, Pasteur’s quadrant research (see Donald E. Stokes, “Pasteur’s Quadrant: Basic Science and Technological Innovation” [4]. Stokes divides research into four quadrants based on its relationship to (a) the quest for fundamental understanding and (b) considerations for use. Research that is essentially a quest for fundamental understanding without consideration of use is pure basic research similar to the physics research of Niels Bohr. Research that utilizes already existing fundamental knowledge to create new products or processes for use is purely applied research similar to that conducted by Thomas Edison. Research that seeks to extend the frontiers of understanding but is also inspired by considerations of use defines Louis Pasteur’s quadrant; research enhancing basic knowledge that has immediate utility). Fundamental yet use-inspired research has had a natural home at the NIH with the great expansion of Government funding for science following World War II. However, there is not a large cadre of Viruses 2020, 12, 1469 3 of 12 scientists trained to intentionally perform such work to quickly apply it, so it usually requires building coalitions/collaborations of scientists with different skills and original interests, and with the latest novel, cutting edge technologies (in recognition of this need, a new institute within NIH, the National Center for Advancing Translational Sciences (NCATS; [5]) was established in 2011. NCATS’ mission is to catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions. However, mostly it has focused on therapeutics development, and vaccine developers have yet to access it fully). Additionally, it is not always clear what scientific disciplines or specific basic research will provide the answers needed. It requires broad but pragmatic, original thinking. Finding, interesting and then recruiting and teaming for a long-term effort such scientists of high quality is one of the funders’ challenges. In addition to obtaining funding, there are other hurdles that hinder scientists moving into a new and challenging